To explore the usefulness of the Lowenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) [Crocco et al, 2013], a novel memory-based cognitive stress test capitalizing on semantic interference, in Huntington’s Disease (HD).

12 healthy adults (HA) and 14 individuals with manifest HD were administered the LASSI-L as part of an annual research visit with the UCSD Huntington’s Disease Clinical Research Center (HDCRC.) Participants in each group were well matched with regard to age and education. Individuals with manifest HD had an average MoCA score of 26, total functional capacity score of 10, and total motor score of 21 suggesting that they were in the early stages of HD. The LASSI-L examines different types of semantic interference that occur in the learning/encoding process. There are free and cued recall trials for two lists of semantically related words with certain trials specific to different aspects of semantic interference including proactive, retroactive, and failure to recover from proactive interference. T-tests for all recall trials and number of intrusions for each trial were conducted between HA and those with HD to examine whether HD renders one more prone to semantic interference in both encoding and retrieval memory processes.

Individuals with HD recalled fewer words on average than HA across all recall trials except for the initial free recall of the first word list. HD individuals recalled significantly fewer (∼1.5) words during the initial (t=-2.8, p=.005, Cohen’s d=2.7) and secondary (t=-2.9, p=.003, Cohen’s d=2.6) cued recall trials from the words on the first list. Individuals with HD also recalled significantly fewer words on initial free recall (t=-2.9, p=.003, Cohen’s d=2.6) and cued recall trials of the second list, with the initial cued recall (t=-2.8, p=.005, Cohen’s d=3.1) sensitive to proactive semantic interference and the second cued recall (t=-3.3, p=.001, Cohen’s d=2.6) sensitive to failure to recover from proactive semantic interference. In addition, individuals with HD also recalled significantly fewer (∼2.2) words on delayed cued recall of the first list, a measure of retroactive semantic interference, than HA (t=-4.8, p<.001, Cohen’s d=2.4). Lastly, individuals with HD recalled fewer (∼4.1) words than HA on delayed free recall of both word lists (t=-3.5, p<.001, Cohen’s d=5.9). The groups did not differ significantly with regard to number of total intrusions per trial.

Overall, our study supports the usefulness of the LASSI-L for neuropsychological assessment of HD in clinical and research settings. In comparison to a demographically similar group of HA, individuals with manifest HD showed significant differences in frontally mediated retrieval processes as well as semantic interference processes that affect efficient encoding of novel information.

To assess the utility of the Mini Mental State Exam (MMSE) and Montreal Cognitive Assessment (MoCA) for tracking cognitive changes Huntington’s Disease.

Currently, the most frequently used brief assessment of global cognitive functioning is the MMSE. Although the MMSE is helpful for distinguishing individuals without significant cognitive impairment from those with dementia, it is not particularly sensitive to more subtle cognitive deficits. The MoCA is another brief cognitive screening tool that has been shown to be more sensitive to mild impairment and may have greater usefulness in subcortical dementias because of its more extensive assessment of executive function. Although the MoCA appears to have high sensitivity and specificity in a variety of neurological populations, there is currently little known about its efficacy in tracking cognitive decline in individuals with HD. We used a mixed effects model to analyze MMSE and MoCA scores collected prospectively during 5 years of follow-up for 163 patients with HD seen at one academic HDSA Center of Excellence. Baseline mean age for the HD cohort was 51.35 years, mean education 14.46 years, and a mean CAG repeat length 43.95. Mean follow-up time was 3.33 years.

Mean MMSE and MoCA scores at baseline were 25.13 (SD=1.66) and 22.76 (SD=3.70) respectively. At baseline, age and gender were not associated with MMSE and MoCA scores, while years of education were. Neither age nor gender predicted rate of decline for the MoCA while years of education predicted rate of decline for the MMSE. For the MMSE, each year of education predicted on average 0.51 points higher score at enrollment; for the MoCA, each year of education predicted on average 0.79 points higher score at enrollment. The mean rates of decline on the MMSE was 0.48 points per year (p<.001) while that on the MoCA was only 0.31 points annually (p<.001) in the first five years of observation.

The MMSE and MoCA decline significantly over time in an unselected HD population. The smaller rate of decline in the MoCA may be due, in part, to the greater variability in baseline, MoCA (SD=3.70) vs MMSE (SD=1.66) scores in our HD cohort. Unlike cortical dementias, such as Alzheimer’s disease (AD), where declines of 2-3 points per year have been described for the MMSE and MoCA, much lower annual rates of decline have been reported in subcortical dementias such as Parkinson’s disease. To our knowledge, this is the first report of rate of cognitive decline on the MMSE and MoCA in HD: such information is vital for adequately preparing patients and families for future needs, in addition to planning for interventional/treatment trials in HD.

Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.

The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.

The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.

Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.